JP2012521975A - Derivatives of 3-alkoxy-4,5-diarylthiophene-2-carboxamide, its preparation and therapeutic use thereof - Google Patents

Abstract

（式中、−Ｒ_１は、−ＮＲ_５Ｒ_６基；非置換の、または置換されているフェニルであり；−Ｒ_２は、（Ｃ_１−Ｃ_４）アルキル；−Ｘ−Ｒ_７基であり；−Ｒ_３およびＲ_４はそれぞれ独立して、置換されているフェニルであり；−Ｒ_５は、水素原子または（Ｃ_１−Ｃ_４）アルキルであり；−Ｒ_６は、非置換の、または置換されている（Ｃ_１−Ｃ_４）アルキルであり；−またはＲ_５およびＲ_６は、これらが結合している窒素原子と一緒になって、非置換の、または置換されている複素環化合物を構成し；−Ｘは、（Ｃ_１−Ｃ_５）アルキレンであり；−Ｒ_７は、−ＯＲ_８基、−ＮＲ_９Ｒ_１０基または−ＳＯ_２−（Ｃ_１−Ｃ_４）アルキル基であり；−Ｒ_８は、水素原子または（Ｃ_１−Ｃ_４）アルキルであり；−Ｒ_９は、水素原子または（Ｃ_１−Ｃ_４）アルキルであり；−Ｒ_１０は、水素原子、−ＣＯＲ_１１基、−ＳＯ_２Ｒ_１１基または−ＣＯ（ＣＨ_２）_ｍＯＨ基であり；−Ｒ_１１は、非置換の、または置換されている（Ｃ_１−Ｃ_４）アルキルであり；−ｍは、１、２または３である。）の化合物に関する。本発明はまた、式（Ｉ）の化合物の調製方法およびこの治療的使用に関する。The present invention relates to a compound of formula (I)

(Wherein —R ₁ is an —NR ₅ R ₆ group; unsubstituted or substituted phenyl; —R ₂ is (C ₁ -C ₄ ) alkyl; —X—R ₇ group; There; -R ₃ and _{R 4} are each independently a phenyl substituted; is -R _5, a hydrogen atom or a _(C 1 -C ₄₎ alkyl; -R ₆ is unsubstituted, Or substituted (C ₁ -C ₄ ) alkyl;-or R ₅ and R ₆ together with the nitrogen atom to which they are attached, an unsubstituted or substituted heterocycle —X is (C ₁ -C ₅ ) alkylene; —R ₇ is —OR ₈ group, —NR ₉ R ₁₀ group or —SO ₂ — (C ₁ -C ₄ ) alkyl group in it; -R ₈ is a hydrogen atom or a _(C 1 -C ₄₎ alkyl; -R ₉ are It is hydrogen atom or a _(C 1 -C ₄₎ alkyl; _{-R 10} represents a hydrogen atom, -COR _{11 group,} be -SO _{2 R 11} group or -CO _{(CH 2)} m OH groups; _{-R 11} is , Unsubstituted or substituted (C ₁ -C ₄ ) alkyl; -m is 1, 2 or 3.). The invention also relates to a process for the preparation of compounds of formula (I) and to their therapeutic use.

Description

  The subject of the present invention is a 3-alkoxy-4,5-diarylthiophene-2-carboxamide derivative, its preparation and its therapeutic use.

Diphenylpyrazole derivatives having affinity for the cannabinoid CB ₁ receptor are described in particular in the patents US5624941, EP0576357, EP0656354 and EP1150961.

5,6-Diphenyl-2-pyrazinecarboxamide derivatives are described in the international application WO 03/051850 as CB ₁ receptor antagonists.

1,2-Diphenyl-4-imidazolecarboxamide derivatives are described in international patent application WO 03/027076 as agonists, partial agonists or antagonists of the CB ₁ receptor.

  4,5-Diarylthiophene derivatives having analgesic properties are described in international application WO 91/19708.

Other 4,5-diarylthiophene derivatives are described as international applications WO2005 / 035488, WO2006 / 070106, WO2006 / 073720 and WO2006 / 084975 as CB ₁ receptor antagonists.

US Pat. No. 5,624,941 European Patent No. 0576357 European Patent No. 0656354 European Patent No. 1150961 International Publication No. 03/051850 International Publication No. 03/027076 International Publication No. 91/19708 International Publication No. 2005/035488 International Publication No. 2006/070106 International Publication No. 2006/073320 International Publication No. 2006/084975

A novel 3-alkoxy-4,5-diarylthiophene-2-carboxamide derivative has now been found that possesses cannabinoid CB ₁ receptor antagonist properties and carries a specific substituent at the 3-position of the thiophene ring. In particular, these novel derivatives have antagonist properties with respect to the peripheral CB ₁ receptors, showing a weak penetration into the brain.

  Accordingly, the subject of the present invention is the formula (I):

（式中、
− Ｒ_１は、
・−ＮＲ_５Ｒ_６基；
・非置換の、またはハロゲン原子、（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）アルコキシおよびトリフルオロメチルから独立して選択される置換基により１回以上置換されているフェニル
を表し；
− Ｒ_２は、
・（Ｃ_１−Ｃ_４）アルキル；
・−Ｘ−Ｒ_７基
を表し；
− Ｒ_３およびＲ_４は、ハロゲン原子、（Ｃ_１−Ｃ_４）アルキル、（Ｃ_１−Ｃ_４）アルコキシおよびトリフルオロメチルから独立して選択される置換基により１回以上置換されているフェニルをそれぞれ独立して表し；
− Ｒ_５は、水素原子または（Ｃ_１−Ｃ_４）アルキルを表し；
− Ｒ_６は、非置換の、または１個以上のフッ素原子により、もしくは非置換の、もしくはハロゲン原子により置換されているフェニルにより置換されている（Ｃ_１−Ｃ_４）アルキルを表し；
− またはそうでなければ、Ｒ_５およびＲ_６は、これらが結合している窒素原子と一緒になって、アゼチジン、ピロリジンおよびピペリジンから選択される複素環を構成し、前記複素環は、非置換であり、またはハロゲン原子により１回以上置換されており；
− Ｘは、（Ｃ_１−Ｃ_５）アルキレンを表し；
− Ｒ_７は、−ＯＲ_８基、−ＮＲ_９Ｒ_１０基または−ＳＯ_２−（Ｃ_１−Ｃ_４）アルキル基を表し；
− Ｒ_８は、水素原子または（Ｃ_１−Ｃ_４）アルキルを表し；
− Ｒ_９は、水素原子または（Ｃ_１−Ｃ_４）アルキルを表し；
− Ｒ_１０は、水素原子、−ＣＯＲ_１１基、−ＳＯ_２Ｒ_１１基または−ＣＯ（ＣＨ_２）_ｍＯＨ基を表し；
− Ｒ_１１は、非置換の、または１個以上のフッ素原子により置換されている（Ｃ_１−Ｃ_４）アルキルを表し；
− ｍは、１、２または３を表す。）
に対応する化合物である。

(Where
-R ₁ is
· _-NR 5 _{R 6} groups;
Represents a phenyl which is unsubstituted or substituted one or more times by a substituent independently selected from a halogen atom, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy and trifluoromethyl. ;
-R ₂ is
· _(C 1 -C ₄₎ alkyl;
-Represents -X-R ₇ group;
-R ₃ and R ₄ are phenyl substituted one or more times by a substituent independently selected from a halogen atom, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy and trifluoromethyl. Represents each independently;
- R ₅ represents a hydrogen atom or a _(C 1 -C ₄₎ alkyl;
-R ₆ represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted by one or more fluorine atoms or by phenyl which is unsubstituted or substituted by a halogen atom;
-Or else R ₅ and R ₆ together with the nitrogen atom to which they are attached constitute a heterocycle selected from azetidine, pyrrolidine and piperidine, said heterocycle being unsubstituted Or is substituted one or more times by a halogen atom;
- X _represents a _(C 1 -C ₅₎ alkylene;
- R ₇ is ₈ group _-OR, -NR _{9 R 10} group or _{-SO 2 - (C 1 -C 4} ) alkyl group;
- R ₈ represents a hydrogen atom or a _(C 1 -C ₄₎ alkyl;
- R ₉ represents a hydrogen atom or a _(C 1 -C ₄₎ alkyl;
- R ₁₀ represents a hydrogen atom, -COR _{11 group,} -SO _{2 R 11} group or -CO the _{(CH 2)} m OH groups;
-R ₁₁ represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted by one or more fluorine atoms;
-M represents 1, 2 or 3. )
It is a compound corresponding to.

  The compound of formula (I) may contain one or more asymmetric carbon atoms. Thus, the compounds of formula (I) can exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers and also their mixtures, including racemic mixtures, are part of the present invention.

  The compounds of formula (I) can exist in the form of bases or in the form of addition salts with acids. Such addition salts are part of the present invention.

  These salts are advantageously prepared using pharmaceutically acceptable salts, although other acid salts used in the purification or isolation of compounds of formula (I) are also part of this invention. is there.

  The term “halogen atom” shall mean bromine, chlorine, fluorine or iodine.

The term “(C ₁ -C ₄ ) alkyl” is a straight or branched alkyl group containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or It shall mean a tert-butyl group.

The term “(C ₁ -C ₅ ) alkylene” is intended to mean a divalent group containing 2 to 5 carbon atoms, for example a methylene, ethylene, trimethylene or tetramethylene group or a pentamethylene group.

The term “(C ₁ -C ₄ ) alkoxy” is a straight or branched alkoxy group containing 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert -It means a butoxy group.

The term “(C ₃ -C ₇ ) cycloalkyl” is intended to mean a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl carbon-based group.

According to the invention, preferably
-R ₁ is
· _-NR 5 _{R 6} groups;
Represents phenyl;
R ₂ is
Methyl;
-Represents -X-R ₇ group;
-R ₃ and R ₄ each independently represent phenyl substituted once or twice by a halogen atom;
-R ₅ represents a hydrogen atom;
-R ₆ represents (C ₁ -C ₄ ) alkyl substituted by one or more fluorine atoms or by phenyl which is unsubstituted or substituted by a halogen atom;
-Or otherwise, R ₅ and R ₆ together with the nitrogen atom to which they are attached, an unsubstituted or substituted piperidin-1-yl group once or twice by a halogen atom Comprising:
- X is _represents a _(C 1 -C ₃₎ alkylene;
- R ₇ is, represents the ₈ group _-OR, -NR _{9 R 10} group or _-SO 2 -CH ₃ group;
-R ₈ represents a hydrogen atom;
-R ₉ represents a hydrogen atom;
- R ₁₀ is a hydrogen atom, -CO-CH ₃ group _represents -SO 2 -CH ₃ group or -COCH ₂ OH groups,
Mention may be made of the compounds of formula (I) in the form of bases or addition salts with acids.

Particularly preferably,
-R ₁ is
_{· -NH (CH 2) 2 -CF} 3 group, 4-fluorobenzyl group, benzylamino group, piperidin-1-yl group, 4,4-difluoro-1-yl group;
Represents phenyl;
R ₂ is
Methyl;
-Represents -X-R ₇ group;
-R ₃ represents 4-chlorophenyl;
-R ₄ represents 2-chlorophenyl or 2,4-dichlorophenyl;
-X represents methylene, ethylene or trimethylene;
- R ₇ is, represents an -OH group, -NH ₂ group, -NHCOCH ₃ group, -NHSO ₂ CH ₃ group, -NHCOCH ₂ OH group or a _-SO 2 -CH ₃ group,
Mention may be made of the compounds of formula (I) in the form of bases or addition salts with acids.

  Among the compounds according to the invention, in particular the following compounds can be mentioned as such and also as their salts:

  In the following description, the term “protecting group Pg” refers firstly to protecting reactive functional groups such as hydroxyl or amine during synthesis and secondly regenerating intact reactive functional groups at the end of the synthesis. It shall mean a possible group. Examples of protecting groups and also methods of protection and deprotection are described in “Protective Group in Organic Synthesis”, Green et al., 4th edition, John Wiley & Sons, Inc. , New York, 2007.

  In the following description, the term “leaving group” is intended to mean a group that can be easily cleaved from a molecule by breaking a heterogeneous bond from which an electron pair leaves. Thus, this group can be easily replaced by another group, for example, during a substitution reaction. Such leaving groups are, for example, halogen or activated hydroxyl groups such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, triflate, acetate and the like. Examples of leaving groups and also references for their preparation are described in “Advanced Organic Chemistry”, M.M. B. Smith and J.M. March, 6th edition, Wiley Interscience, 2007, pages 497-501.

According to the invention, the compound of formula (I) is
formula:

（式中、Ｒ_１、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義した通りである。）の化合物を、塩基の存在下で、式：
Ｚ−Ｒ_２（ＩＩＩ）
（式中、Ｒ_２は、式（Ｉ）の化合物について定義した通りであり、およびＺは、上述の脱離基を表す。）の化合物と反応させることを特徴とする方法により調製することができる。

In which R ₁ , R ₃ and R ₄ are as defined for the compound of formula (I) in the presence of a base:
Z-R ₂ (III)
(Wherein R ₂ is as defined for the compound of formula (I), and Z represents the above-mentioned leaving group). it can.

  Optionally, the compound of formula (I) is converted into one of this addition salt with an acid.

  The reaction is carried out in a solvent such as acetone, acetonitrile or N, N-dimethylformamide in the presence of a base such as an alkali metal carbonate such as cesium carbonate or sodium carbonate, at a temperature from ambient temperature to the reflux temperature of the solvent. In the implementation.

According to one variant of the method:
formula:

（式中、Ｒ_２、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義の通りである。）の酸またはこの酸の官能性誘導体を、式：

Wherein R ₂ , R ₃ and R ₄ are as defined for the compound of formula (I), or a functional derivative of this acid of the formula:

（式中、Ｒ_１は、式（Ｉ）の化合物について定義の通りである。）の化合物と反応させる。

(Wherein R ₁ is as defined for the compound of formula (I)).

  Optionally, the compound of formula (I) thus obtained is converted into one of the salts.

  When the compound of formula (V) is treated with the acid of formula (IV) itself, the method can be used for coupling agents used in peptide chemistry, such as 1,3-dicyclohexylcarbodiimide or benzotriazol-1-yloxy. Tris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate or 2- (lH-benzotriazol-1-yl) -1,1,3,3-tetra In the presence of methyluronium tetrafluoroborate, in the presence of a base such as triethylamine, N, N-diisopropylethylamine or 4-dimethylaminopyridine, a solvent such as dichloromethane, dichloroethane, N, N-dimethylformamide. Or in tetrahydrofuran, carried out at a temperature between the reflux temperature of the solvent -10 ° C..

Functional derivatives of the acid (IV) include acid chlorides, anhydrides in mixed anhydrides, C ₁ -C ₄ alkyl esters or activated esters in which the alkyl is linear or branched, eg p-nitrophenyl Esters can be used.

  Thus, in the process according to the invention, an acid chloride obtained by reacting thionyl chloride or oxalyl chloride with an acid of formula (IV) is converted to a compound of formula (V) with a solvent, for example a chlorinated solvent (for example Tertiary in dichloromethane, dichloroethane or chloroform), ether (eg tetrahydrofuran or dioxane) or amide (eg N, N-dimethylformamide) at a temperature between 0 ° C. and ambient temperature under an inert atmosphere. The reaction can also be carried out in the presence of an amine, for example triethylamine, N-methylmorpholine or pyridine.

  One variation is to prepare a mixed anhydride of an acid of formula (IV) by reacting ethyl chloroformate with an acid of formula (IV) in the presence of a base, for example triethylamine, and the anhydride. Is reacted with a compound of formula (V) in a solvent, for example dichloromethane, under an inert atmosphere at ambient temperature in the presence of a base, for example triethylamine.

According to another variant of the method, R ₂ represents a —X—R ₇ group and R ₇ represents a —NR ₉ R ₁₀ group, R ₁₀ = —COR ₁₁ or R ₁₀ = —CO (CH ₂ ) Compounds of formula (I) that are _m OH can be prepared from compounds of formula (I) where X—NR ₉ R ₁₀ ═X—NR ₉ H. The latter compound is the procedure described above for the reaction of an acid of formula R ₁₁ —COOH (VI) or formula HO— (CH ₂ ) _m —COOH (VII) with a compound of formula (IV) of formula (V). It reacts according to conditions.

According to another variant of the method, the compound of formula (I) wherein R ₂ represents a —X—R ₇ group and R ₇ represents a —NR ₉ R ₁₀ group and R ₁₀ = —SO ₂ R ₁₁ compound _can be prepared from compounds of formula (I) wherein _{X-NR 9 R 10 = X} -NR 9 H. The latter compound is reacted with a compound of the formula Hal-SO ₂ R ₁₁ (VIII), wherein Hal represents a halogen atom, preferably chlorine. The reaction is carried out in the presence of a base such as triethylamine in a solvent such as dichloromethane at a temperature between 0 ° C. and ambient temperature.

  Subsequently, the compound of formula (I) obtained via various procedures can be separated from the reaction medium and purified by conventional methods, for example by crystallization or chromatography.

  The compound of formula (II) has the formula:

（式中、Ｒ_１、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義した通りであり、およびＷは、（Ｃ_１−Ｃ_４）アルキルを表す。）の化合物を、例えば、トリブロモボランと、溶媒、例えば、ジクロロメタンなどの中で、−６０℃から周囲温度の間の温度において反応させることにより調製する。

Wherein R ₁ , R ₃ and R ₄ are as defined for the compound of formula (I) and W represents (C ₁ -C ₄ ) alkyl. Prepared by reacting with bromoborane in a solvent such as dichloromethane at a temperature between −60 ° C. and ambient temperature.

  Compounds of formula (III) are known and are commercially available or are prepared by methods known to those skilled in the art.

  The compound of formula (IV) has the formula:

（式中、Ｒ_２、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義した通りであり、およびＹは、（Ｃ_１−Ｃ_２）アルコキシ基を表す。）の化合物の鹸化により調製する。従って、例えば、Ｙ＝−ＯＣＨ_３の場合、反応は、水酸化ナトリウムの作用により、溶媒、例えば、メタノール、Ｎ，Ｎ−ジメチルホルムアミドまたはこれらの溶媒の混合物中で、周囲温度から溶媒の還流温度の間の温度において実施する。

(Wherein R ₂ , R ₃ and R ₄ are as defined for the compound of formula (I) and Y represents a (C ₁ -C ₂ ) alkoxy group). To do. Thus, for example, when Y = —OCH ₃ , the reaction is effected by the action of sodium hydroxide in a solvent such as methanol, N, N-dimethylformamide or a mixture of these solvents from ambient temperature to the reflux temperature of the solvent At a temperature between.

The compounds of the formula (V) are known or known methods, for example EP 0428434, EP0512901, EP0515240, WO96 / 23787, WO02 / 094821, WO03 / 104225 and WO2006 / 021654 or J.P. Med. Chem. , 1964, 7 , 619-622 and J.A. Org. Chem. , 1990, 55 , 4207-4209.

  Compounds of formula (V) are generally prepared in a protected form on the piperidine nitrogen atom; after the deprotection step, the expected compound of formula (V) is obtained.

  Compounds of formula (VI), (VII) and (VIII) are known, commercially available or prepared by methods known to those skilled in the art.

  The compound of formula (IX) has the formula:

（式中、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義の通りであり、およびＷは、（Ｃ_１−Ｃ_４）アルキルを表す。）の酸またはこの酸の官能性誘導体を式（Ｖ）の化合物と、式（ＩＶ）の化合物の式（Ｖ）の化合物との反応について上述した操作条件により反応させることにより調製する。

Wherein R ₃ and R ₄ are as defined for the compound of formula (I), and W represents (C ₁ -C ₄ ) alkyl. An acid or a functional derivative of this acid Prepared by reacting the compound of formula (V) with the compound of formula (IV) under the operating conditions described above for the reaction of the compound of formula (V).

  The compound of formula (X) has the formula:

（式中、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義した通りであり、およびＹは、（Ｃ_１−Ｃ_２）アルコキシを表す。）の化合物を式（ＩＩＩ）の化合物と、化合物（ＩＩ）の化合物の式（ＩＩＩ）の化合物との反応について上述した操作条件により反応させることにより調製する。

Wherein R ₃ and R ₄ are as defined for the compound of formula (I) and Y represents (C ₁ -C ₂ ) alkoxy. The compound of formula (III) Prepared by reacting the compound of compound (II) with the compound of formula (III) under the operating conditions described above.

  The compound of formula (XI) has the formula:

（式中、Ｒ_３およびＲ_４は、式（Ｉ）の化合物について定義した通りであり、Ｗは、（Ｃ_１−Ｃ_４）アルキルを表し、およびＹは、（Ｃ_１−Ｃ_２）アルコキシを表す。）の化合物を、式（Ｘ）の化合物の鹸化について上述した方法により鹸化することにより調製する。

Wherein R ₃ and R ₄ are as defined for the compound of formula (I), W represents (C ₁ -C ₄ ) alkyl, and Y represents (C ₁ -C ₂ ) alkoxy Is prepared by saponification by the method described above for saponification of the compound of formula (X).

  A compound of formula (XII) is prepared by reacting a compound of formula (XIII) with, for example, tribromoborane, under the operating conditions described above for the preparation of the compound of formula (II).

Compounds of formula (XIII) are prepared according to Scheme I below, where Hal represents a halogen atom, preferably bromine, Y represents (C ₁ -C ₂ ) alkoxy, and W represents (C ₁ -C ₄₎ alkyl, preferably methyl.

スキームＩの段階ａ１において、式（ＸＶＩ）の化合物を式Ｗ−Ｈａｌ（ＸＶＩＩ）の化合物と、塩基、例えば、アルカリ金属炭酸塩、例えば、炭酸カリウムの存在下で、溶媒、例えば、Ｎ，Ｎ−ジメチルホルムアミド中で、周囲温度から溶媒の還流温度の間の温度において反応させる。

In step a1 of Scheme I, a compound of formula (XVI) is converted to a compound of formula W-Hal (XVII) and a solvent such as N, N in the presence of a base such as an alkali metal carbonate such as potassium carbonate. React in dimethylformamide at a temperature between ambient temperature and the reflux temperature of the solvent.

In step b1, the compound of formula (XV) thus obtained is converted in a basic medium with a boronic acid of formula R ₄ —B (OH) ₂ (XVIII), for example an alkali metal carbonate, such as sodium carbonate, etc. In the presence of a palladium complex, such as tetrakis (triphenylphosphine) palladium, in a solvent such as toluene, tetrahydrofuran or dioxane, at a temperature between ambient temperature and the reflux temperature of the solvent.

In step c1, the compound of formula (XIV) thus obtained is reacted with a boronic acid of formula R ₃ —B (OH) ₂ (XIX) under the conditions described above in step b1.

  Compounds of formula (XVI), (XVII), (XVIII) and (XIX) are known, commercially available or prepared by methods known to those skilled in the art.

  The following examples describe the preparation of certain compounds according to the present invention. These examples do not limit the invention, but merely illustrate the invention. The numbers of the exemplified compounds refer to the numbers listed in the following Tables (I) and (II) illustrating the chemical structure and physical properties of some compounds according to the present invention.

The following abbreviations are used in the preparation examples and examples:
EtOAc: ethyl acetate BBR _3: Boron tribromide Cs ₂ CO _3: Cesium carbonate DCM: Dichloromethane DMSO: Dimethyl sulfoxide DMF: N, N-dimethylformamide Bp: boiling ether: diethyl ether 2N hydrochloric ether: diethyl ether 2N hydrochloric acid solution Isoether: Diisopropyl ether Mp: Melting point HPLC: High performance liquid chromatography UPLC: Ultra high performance liquid chromatography MeOH: Methanol Silica H: Silica gel 60H sold by Merck (DARMSTAD)
Buffer solution (pH = 2): 16.66 g KHSO ₄ and 32.32 g K ₂ SO ₄ in 1 liter in water AT: ambient temperature TBTU: O-benzotriazol-1-yl-N, N, N ′ , N′-Tetramethyluronium tetrafluoroborate TFA: trifluoroacetic acid THF: tetrahydrofuran tetrakis: tetrakis (triphenylphosphine) palladium Nuclear magnetic resonance spectra are recorded in DMSO-d6. The following abbreviations are used to interpret the spectrum: s: singlet, d: doublet, t: triplet, q: quartet, qui: quintet, m: unresolved peak, bs: broad Single line, sd: split double line.

The compounds according to the invention are analyzed by linked LC / UV / MS (liquid chromatography / UV detection / mass spectrometry). Characteristic molecular peak (MH ⁺ ) and retention time (rt) (min (min)) are measured.

  Compounds are analyzed by coupled HPLC-UV-MS or otherwise UPLC-UV-MS (liquid chromatography-UV detection and mass detection).

The analysis conditions are as follows:
Condition A (HPLC) :
A Symmetry C18 (50 × 2.1 mm; 3.5 μm) column is used.

Eluent A: 0.005% TFA in water, about pH 3.1
Eluent B: 0.005% TFA in acetonitrile
Slope:

カラム温度：３０℃；流速：０．４ｍｌ／分。
検出：λ＝２１０ｎｍ−２２０ｎｍ

Column temperature: 30 ° C .; flow rate: 0.4 ml / min.
Detection: λ = 210nm-220nm

Condition B (HPLC) :
An XTerra MS C18 (50 × 2.1 mm; 3.5 μm) column is used.

Eluent A: 10 mM AcONH ₄ , about pH 7
Eluent B: Acetonitrile Gradient:

カラム温度：３０℃；流速：０．４ｍｌ／分。
検出：λ＝２２０ｎｍ

Column temperature: 30 ° C .; flow rate: 0.4 ml / min.
Detection: λ = 220nm

Condition C (UPLC) :
An Acquity BEH C18 (50 × 2.1 mm; 1.7 μm) column is used.
Eluent A: 0.005% TFA in water, about pH 3.1 / acetonitrile (97/3)
Eluent B: 0.035% TFA in acetonitrile
Slope:

カラム温度：４０℃；流速：１ｍｌ／分。
検出：λ＝２２０ｎｍ

Column temperature: 40 ° C .; flow rate: 1 ml / min.
Detection: λ = 220nm

Mass spectrometric mass spectra are recorded in positive electrospray (ESI) mode to produce adducts with ions (MH ⁺ ) or other cations obtained from protonation of the analyte, eg, Na ⁺ , K ^+, etc. Observe the ions obtained from.

Preparation example
1—Preparation Example of Compound of Formula (XIII)
Preparation Example 1.1 :
Methyl 4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3-methoxythiophene-2-carboxylate

A) Methyl 4,5-dibromo-3-methoxythiophene-2-carboxylate 9.97 ml of a solution of iodomethane, then 29.44 g of K ₂ CO ₃ with 34.35 g of methyl 4,5-dibromo-3-hydroxy Thiophene-2-carboxylate is added dropwise to a solution of 150 ml in DMF and the mixture is left stirring at AT for 18 hours. After cooling, the reaction mixture is diluted in 100 ml of ethyl ether, filtered and the filtrate is concentrated in vacuo. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane / EtOAc mixture (85/15; v / v). 28.70 g of the expected compound are obtained.

B) Methyl 4-bromo-5- (2,4-dichlorophenyl) -3-methoxythiophene-2-carboxylate To a solution of 28.70 g of compound of step A) in 110 ml of toluene, 16.60 g of (2, 4-Dichlorophenyl) boronic acid is added and then 87 ml of a 2M solution of Na ₂ CO ₃ is added dropwise. Argon is diffused into the reaction mixture for 30 minutes, then 5.03 g of tetrakis is added and the mixture is heated at 110 ° C. for 18 hours. After cooling to AT, 80 ml distilled water was added to the reaction mixture, extraction was carried out with 80 ml EtOAc, dehydration was carried out with Na ₂ SO ₄ and the solvent was distilled off under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane / EtOAc mixture (85/15; v / v). 16.21 g of the expected compound are obtained.

C) Methyl 4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3-methoxythiophene-2-carboxylate To a solution of 16.21 g of compound in step B) in 110 ml of toluene, 7.75 g Of (4-chlorophenyl) boronic acid is added, followed by dropwise addition of 40.93 ml of a 2M solution of Na ₂ CO ₃ . Argon is diffused into the reaction mixture for 30 minutes, then 2.36 g of tetrakis is added and heating is carried out at 110 ° C. for 18 hours. After cooling to AT, the reaction mixture was washed with 80 ml distilled water, then extraction was carried out with 80 ml EtOAc, dehydration was carried out with Na ₂ SO ₄ and the solvent was distilled off under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with heptane and then with a heptane / EtOAc mixture (85/15; v / v). 13.23 g of the expected compound are obtained.

Preparation Example 1.2 :
Methyl 5- (2-chlorophenyl) -4- (4-chlorophenyl) -3-methoxythiophene-2-carboxylate

A) Methyl 4-bromo-5- (2-chlorophenyl) -3-methoxythiophene-2-carboxylate 11.39 g of compound of Step A) of Preparation 1.1, 5.56 g 2-chlorophenylboronic acid and 34.52 ml of a 2M solution of sodium carbonate is added to 60 ml of toluene. Argon is bubbled for 30 minutes before adding 1.99 g of tetrakis. Heating is performed at 110 ° C. overnight. After returning to ambient temperature, 60 ml of distilled water are added, the mixture is extracted with 60 ml of ethyl acetate, the organic phase is dried and evaporated. The product obtained is purified by chromatography on silica (eluent: heptane / ethyl acetate (80/20; v / v)). 7.84 g of the expected compound are obtained.

B) Methyl 5- (2-chlorophenyl) -4- (4-chlorophenyl) -3-methoxythiophene-2-carboxylate 7.84 g of compound of step A), 4.10 g 4-chlorophenylboronic acid and 21. 68 ml of a 2M solution of sodium carbonate is added to 60 ml of toluene. Argon is bubbled for 30 minutes before adding 1.25 g of tetrakis. Heating is performed at 110 ° C. overnight. After returning to ambient temperature, 60 ml of distilled water are added, the mixture is extracted with 60 ml of ethyl acetate, the organic phase is dried and evaporated. The product obtained is purified by chromatography on silica (eluent: heptane / ethyl acetate (80/20; v / v)). 4.90 g of the expected compound are obtained.

2-Preparation example of compound of formula (XI)
Preparation Example 2.1 :
4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methoxythiophene-2-carboxylic acid

  1.86 g NaOH pellets are added to a mixture of 13.23 g of the compound of Preparation 1.1 in 60 ml DMF / MeOH mixture (50/50; v / v) and heating is carried out at 80 ° C. for 18 hours. . The product obtained is evaporated to dryness, the residue is dissolved with 30 ml of distilled water and the aqueous phase is washed with 50 ml of ethyl ether. The aqueous phase is then acidified to pH = 2 by adding HCl, suction filtration and drying are carried out. 12.43 g of the expected compound are obtained.

3- Preparation examples of compounds of formula (IX)
Preparation Example 3.1 :
1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-methoxythien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide

  To a mixture of 2 g of the compound of Preparation 2.1 in 100 ml DCM was added 1.16 g 4-phenylpiperidine-4-carboxamide hydrochloride, followed by dropwise addition of 2.02 ml triethylamine solution and 1.71 g TBTU. Add. The mixture is left stirring at ambient temperature for 1 hour. The solvent is distilled off under vacuum, a buffer solution (pH = 2) is added, the mixture is extracted with EtOAc, the resulting product is dried, filtered and concentrated. The reaction crude is purified by silica gel chromatography, elution being carried out with DCM and then with a DCM / MeOH mixture (90/10; v / v). 1.96 g of the expected compound are obtained.

Preparation Example 3.2 :
4- (Benzylamino) -1-[[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3-methoxy-2-thienyl] carbonyl] piperidine-4-carboxamide

1.34 g of 4- (benzylamino) piperidine-4-carboxamide dihydrochloride, 1.93 ml of triethylamine and 1.4 g of TBTU were added to a mixture of 1.64 g of the compound of Preparation 2.1 in 50 ml of DCM. Add and allow the mixture to stir at ambient temperature for 1 hour. The reaction mixture is concentrated under vacuum, the residue is dissolved with buffer solution (pH = 2), extraction is carried out with EtOAc, the organic phase is dried over MgSO ₄ , filtration is carried out and the solvent is distilled off under vacuum. Leave. The residue is chromatographed on silica gel, elution being carried out with DCM and then with a DCM / MeOH mixture (60/40; v / v). 2.0 g of the expected compound are obtained.

4- Preparation examples of compounds of formula (II)
Preparation Example 4.1 :
1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-hydroxythien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide

  A mixture of 1.81 g of the compound of Preparation 3.1 in 20 ml DCM was cooled to −50 ° C., then 9.05 ml of a 1M solution of tribromoborane was added dropwise and the temperature was allowed to reach AT with stirring for 4 h. Bring it back. The reaction mixture is poured onto ice and the resulting mixture is neutralized to pH = 7 by adding concentrated NaOH, extraction is performed with DCM, and the resulting product is dried and concentrated. The reaction crude is purified by silica gel chromatography, elution being carried out with DCM and then with a DCM / MeOH mixture (97/3; v / v). 0.715 g of the expected compound is obtained.

Preparation Example 4.2 :
1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3-hydroxythien-2-yl] carbonyl} -4-cyclohexylpiperidine-4-carboxamide

  This compound is prepared using 4-cyclohexylpiperidine-4-carboxamide and the compound of Preparation 2.1 according to the procedures described in Preparations 3.1 and 4.1.

Preparation Example 4.3 :
4- (Benzylamino) -1-[[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3-hydroxy-2-thienyl] carbonyl] piperidine-4-carboxamide

A mixture of 2.0 g of the compound of Preparation 3.2 in 40 ml DCM was cooled to −50 ° C., then 9.54 ml of a 1M solution of tribromoborane in DCM was added dropwise and the mixture was brought to a temperature of AT. Stir for 4 hours while returning. The reaction mixture is poured onto ice and the resulting mixture is neutralized to pH = 7 by adding concentrated NaOH, the extraction is carried out with DCM, the organic phase is dried over MgSO ₄ , the filtration is carried out and the solvent Are distilled off under vacuum. The residue is dissolved in iso ether and the precipitate formed is filtered off with suction and dried under vacuum. 1.92 g of the expected compound are obtained.

5- Preparation examples of compounds of formula (XII)
Preparation Example 5.1 :
Methyl 5- (2-chlorophenyl) -4- (4-chlorophenyl) -3-hydroxythiophene-2-carboxylate

  3.35 g of the compound of Preparation 1.2 is added to 20 ml DCM, then the mixture is cooled to −50 ° C. and 6.40 ml BBr3 (1M in DCM) is added dropwise, then the mixture is brought to ambient temperature. return. The mixture is concentrated, the product obtained is dissolved with DCM, washing is carried out with 50 ml of water, drying is carried out and the product obtained is concentrated. The product obtained is purified by chromatography on silica (eluent: heptane / ethyl acetate (80/20; v / v)). 2.47 g of the expected compound are obtained.

6—Preparation Example of Compound of Formula (X)
Preparation Example 6.1 :
Methyl 5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] thiophene-2-carboxylate

0.7 g of the compound of Preparation 5.1, 0.824 g 2- (3-bromopropoxy) tetrahydro-2H-pyran and 1.2 g Cs ₂ CO ₃ were added to 20 ml acetone and the mixture was left overnight Reflux. Filtration is performed and the resulting product is concentrated. The product obtained is purified by chromatography on silica (eluent: heptane / ethyl acetate (60/40; v / v)). 0.950 g of the expected compound is obtained.

7-Preparation examples of compounds of formula (IV)
Preparation Example 7.1 :
5- (2-Chlorophenyl) -4- (4-chlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] thiophene-2-carboxylic acid

A mixture of 0.95 g compound of Preparation 6.1 and 0.29 g NaOH pellets in 40 ml MeOH and 1 ml in water is refluxed for 3 hours. The reaction mixture is concentrated under vacuum, the residue is dissolved in a buffer solution (pH = 2), extraction is carried out with DCM, the organic phase is dried over MgSO ₄ , filtration is carried out and the solvent is removed under vacuum. Distill off. The residue is chromatographed on silica gel, elution being carried out with DCM and then a gradient of the mixture DCM / MeOH to (80/40; v / v). 0.564 g of the expected compound is obtained.

8- Preparation of compounds of formula (V)
Preparation Example 8.1 :
4-[(3,3,3-trifluoropropyl) amino] -4-piperidinecarboxamide

A) tert-butyl 4-carbamoyl-4-[(3,3,3-trifluoropropyl) amino] piperidine-1-carboxylate 10 g tert-butyl 4-amino-4-carbamoylpiperidine-1-carboxylate, 4.42 g 3,3,3-trifluoropropionaldehyde, 17.61 g sodium triacetoxyborohydride and 4.51 ml acetic acid are added to 250 ml DCM at AT, then the mixture is stirred for 3 hours. Water is added, the expected compound is extracted with DCM, and the organic phase is washed with a saturated solution of NaHCO ₃ and then with water. After drying of the organic phase, filtration and evaporation to dryness, 13 g of the expected compound are obtained.

B) 4-[(3,3,3-trifluoropropyl) amino] piperidine-4-carboxamide 13 g of the compound obtained in (A) are stirred in 25 ml of MeOH and then 30 ml of ethereal hydrochloric acid (2M) Is added and the mixture is allowed to stir overnight. After filtration and drying, 9.57 g of the expected compound is obtained.

Preparation Example 8.2 :
4-Phenylpiperidine-4-carboxamide hydrochloride

A) 1-Benzyl-4-phenylpiperidine-4-carboxamide hydrochloride 10 g 1-benzyl-4-phenylpiperidine-4-carbonitrile is added to 77 ml concentrated sulfuric acid and the mixture is then heated at 100 ° C. for 1 hour. . The reaction mixture is then added to ice and then basified with NH ₄ OH. The product is extracted with CH ₂ Cl ₂ , dried and evaporated. After crystallization of the hydrochloride from ether, 5.7 g of the expected product are obtained.

B) 4-Phenylpiperidine-4-carboxamide hydrochloride 5.6 g of the product obtained in (A), 6.7 g of cyclohexadiene and 0.5 g of palladium on carbon (10%) were added to 70 ml of MeOH. The reaction mixture is refluxed for 6 hours. The catalyst is filtered off over celite and the resulting product is evaporated to dryness. After crystallization from an ether-isopropyl ether mixture, 3 g of the expected product are obtained.

  (Example)

Compound No. 6
1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide A) 1 -({4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- [2- (tetrahydro-2H-pyran-2-yloxy) ethoxy] thien-2-yl} carbonyl) -4- Phenylpiperidine-4-carboxamide 0.188 g 2- (2-bromoethoxy) tetrahydro-2H-pyran and 0.294 g Cs ₂ CO ₃ in 20 ml acetone of 0.264 g compound from Preparation 4.1 Add to mixture. The mixture is refluxed for 18 hours. Filtration is performed and the filtrate is concentrated under vacuum. The reaction crude is purified by silica gel chromatography, elution being carried out with DCM and then with a DCM / MeOH mixture (97/3; v / v). 0.272 g of the expected compound is obtained.

B) 1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide Amber List 15 resin is added to a mixture of the previous stage 0.272 g of compound in 15 ml of acetone and then the mixture is refluxed for 2 hours. Filtration and concentration are performed. The reaction crude is purified by silica gel chromatography, elution being carried out with DCM and then with a DCM / MeOH mixture (97/3; v / v). 0.146 g of the expected compound is obtained.

Compound No. 4
1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide Prepared using the compound of Preparation 4.1 and 2- (3-bromopropoxy) tetrahydro-2H-pyran by a procedure similar to that described in Steps A) and B) described in Example 1. .

Compound No. 5
1-({4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3- [3- (methylsulfonyl) propoxy] thien-2-yl} carbonyl) -4-phenylpiperidine-4-carboxamide 0.148 g of 3- (methylsulfonyl) propyl methanesulfonate and 0.294 g of Cs ₂ CO ₃ are added to a mixture of 0.200 g of the compound of Preparation 4.1 in 15 ml of acetone. The mixture is refluxed for 18 hours. Suction filtration and concentration are performed. The reaction crude is purified by silica gel chromatography, elution being carried out with DCM and then with a DCM / MeOH mixture (97/3; v / v). 0.065 mg of the expected compound is obtained.

Compound number 2
1 ′-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {3-[(methylsulfonyl) amino] propoxy} thien-2-yl] carbonyl} -4-cyclohexylpiperidine -4-carboxamide A) tert-butyl [3-({2-[(4-carbamoyl-4-cyclohexylpiperidin-1-yl) carbonyl] -4- (4-chlorophenyl) -5- (2,4-dichlorophenyl ) Thien-3-yl} oxy) propyl] carbamate 0.212 g of tert-butyl (3-bromopropyl) carbamate and 0.290 g of Cs ₂ CO ₃ were added to 20 ml of 0.300 g of compound of Preparation 4.2. To a mixture of acetone in acetone. The mixture is refluxed for 18 hours. Suction filtration and concentration are performed. 0.291 g of the expected compound is obtained.

B) 1-{[3- (3-Aminopropoxy) -4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) thien-2-yl] carbonyl} -4-cyclohexylpiperidine-4-carboxamide 5 ml Is added dropwise to a mixture of the previous step 0.291 g of the compound in 15 ml of DCM. The mixture is left stirring at AT overnight. The reaction mixture is concentrated to dryness, the residue is dissolved in ethyl ether, filtered off with suction and dried. 0.257 g of the expected compound is obtained.

C) 1-{[4- (4-Chlorophenyl) -5- (2,4-dichlorophenyl) -3- {3-[(methylsulfonyl) amino] propoxy} thien-2-yl] carbonyl} -4-cyclohexyl Piperidine-4-carboxamide 0.04 ml of methanesulfonyl chloride solution and 0.18 ml of triethylamine solution are added dropwise to a mixture of 0.257 mg of the previous compound in 10 ml of DCM and the mixture is stirred at AT for 1 hour. deep. The reaction mixture is evaporated to dryness, washing is carried out with 15 ml of distilled water, extraction is carried out with DCM, drying and concentration are carried out. 0.198 g of the expected compound is obtained.

Compound No. 24
4- (Benzylamino) -1-[[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) -2-thienyl] carbonyl] piperidine-4-carboxamide hydrochloride Salt A) 4- (Benzylamino) -1-[[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] -2-thienyl] carbonyl] piperidine-4-carboxamide 0.35 g compound of Preparation Example 4.3, 0.153 g 2- (3-bromopropoxy) tetrahydro-2H-pyran and 0.22 g Cs ₂ CO ₃ Of 15 ml in acetone is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel, elution being carried out with DCM and then a gradient of the mixture DCM / MeOH to (75/25; v / v). 0.3 g of the expected compound is obtained.

B) 4- (Benzylamino) -1-[[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) -2-thienyl] carbonyl] piperidine-4- Carboxamide hydrochloride 30 ml of 2N hydrochloric acid ether solution is added to a mixture of 0.3 g of the previous step in 15 ml of MeOH and the mixture is allowed to stir at AT for 1 hour. The reaction mixture is concentrated in vacuo, the residue is chromatographed on silica gel, elution is carried out with a mixture of (65/35; v / v) to (90/10; v / v) MeOH / H ₂ O. carry out. 0.18 g of the expected compound is obtained after crystallization from iso ether.

Compound No. 26
1- [5- (2-Chlorophenyl) -4- (4-chlorophenyl) -3- [3- (hydroxypropoxy) -2-thienyl] carbonyl] -4-[(4-fluorobenzyl) amino] piperidine-4 -Carboxamide hydrochloride A) 1-[[5- (2-Chlorophenyl) -4- (4-chlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) propoxy] -2-thienyl] carbonyl ] -4-[(4-Fluorobenzyl) amino] piperidine-4-carboxamide 0.3 g compound of Preparation Example 7.1, 0.19 g 4-[(4-fluorobenzyl) amino] piperidine-4-carboxamide A mixture of dihydrochloride, 0.29 ml triethylamine and 0.19 g TBTU in 20 ml DCM was stirred at AT for 1 hour. To keep. The reaction mixture is concentrated in vacuo, the residue is dissolved in 70 ml of buffer (pH = 2), extraction is carried out with DCM, the organic phase is dried over MgSO ₄ , filtration is carried out and the solvent is removed in vacuo. Distill off below. The residue is chromatographed on silica gel, elution being carried out by DCM, followed by a gradient of the mixture DCM / MeOH to (70/30; v / v). 0.35 g of the expected product is obtained.

B) 1- [5- (2-Chlorophenyl) -4- (4-chlorophenyl) -3- [3- (hydroxypropoxy) -2-thienyl] carbonyl] -4-[(4-fluorobenzyl) amino] piperidine -4-carboxamide hydrochloride 30 ml of 2N hydrochloric acid ether solution is added to a mixture of the previous step 0.35 g of compound in 30 ml of MeOH and the mixture is left to stir at AT overnight. The reaction mixture is concentrated under vacuum, the residue is chromatographed on silica gel, elution is carried out with a mixture DCM / MeOH up to (60/40; v / v). 0.186 g of the expected compound is obtained after crystallization from iso ether.

Compound No. 27
1- [5- (2-Chlorophenyl) -4- (4-chlorophenyl) -3- [3- (hydroxypropoxy) -2-thienyl] carbonyl] -4-phenylpiperidine-4-carboxamide A) 1- [5 -(2-Chlorophenyl) -4- (4-chlorophenyl) -3- [3- (tetrahydro-2H-pyran-2-yloxy) thienyl] carbonyl] -4-phenylpiperidine-4-carboxamide of Preparation Example 7.1 A mixture of 0.26 g compound, 0.13 g 4-phenylpiperidine-4-carboxamide hydrochloride, 0.21 ml triethylamine and 0.165 g TBTU in 20 ml DCM is left to stir at AT for 1 hour. The reaction mixture is concentrated in vacuo, the residue is dissolved in 70 ml of buffer (pH = 2), extraction is carried out with DCM, the organic phase is dried over MgSO ₄ , filtration is carried out and the solvent is removed in vacuo. Distill off below. The residue is chromatographed on silica gel, elution being carried out with DCM and then a gradient of the mixture DCM / MeOH to (60/40; v / v). 0.2 g of the expected compound is obtained.

B) 1-{[5- (2-Chlorophenyl) -4- (4-chlorophenyl) -3- (3-hydroxypropoxy) -2-thienyl] carbonyl} -4-phenylpiperidine-4-carboxamide A mixture of 2 g of compound and Amberlyst 15 resin in 30 ml of MeOH is refluxed overnight. The reaction mixture is filtered and the filtrate is concentrated in vacuo. The residue is chromatographed on silica gel, elution being carried out with DCM and then a gradient of the mixture DCM / MeOH to (60/40; v / v). 0.1 g of the expected compound is obtained.

  Tables 1 and 2 show the chemical structures of some compounds according to the invention and also their physicochemical properties (analysis by linked LC / UV / MS: liquid chromatography / UV detection / mass spectrometry). These compounds are prepared by procedures similar to those illustrated above or exemplified compounds (Examples 1-35).

  In these tables, Me represents a methyl group.

The analyzes performed by NMR for compounds 24, 26 and 27 are listed below:
Compound 24: ¹ H NMR: DMSO-d ₆ (250 MHz): δ (ppm): 1.53-1.68: m: 2H; 1.68-2.01: m: 4H; 3.25-3. 34: m: 4H; 3.42-3.98: m: 4H; 3.87: t: 2H; 4.34: t: 1H; 7.10-7.21: m: 3H; 7.22- 7.51: m: 11H; 7.68: d: 1H.

Compound 26: ¹ H NMR: DMSO-d ₆ (250 MHz): δ (ppm): 1.54-1.68: m: 2H; 1.68-2.19: m: 2H; 2.33-2. 58: m: 2H; 3.20-3.40: m: 4H; 3.44-3.71: m: 2H; 3.87: t: 2H; 3.95-4.22: m: 2H; 4.39: bs: 1H; 7.17: d: 3H; 7.22-7.54: m: 9H; 7.65: bs: 1H; 8,06: bs: 1H; 9,62: bs: 1H.

Compound _{^{27: 1 H NMR: DMSO-}} d 6 (250MHz): δ (ppm): 1.46-1.65: m: 2H; 1.74-1.96: m: 2H; 2.50-2. 63: m: 2H; 3.25: bs: 2H; 3.21-3.30: m: 2H; 3.85: t: 2H; 4.7: bs: 2H; 4.35: t: 1H; 7.11: s: 1H; 7.17: d: 2H; 7.22-7.32: m: 2H; 7.32-7.57: m: 10H.

The compounds of formula (I) are described in Under the experimental conditions described by Rinaldi-Carmona et al. (FEBS Letters, 1994, 350 , 240-244) it has a very good affinity for the cannabinoid CB ₁ receptor in vitro (IC ₅₀ ≦ 5 × 10 ⁻⁷ M).

  The antagonistic nature of the compounds of formula (I) is Bouaboula et al., J. MoI. Biol. Chem. 1995, 270, 1397-13980, M .; Rinaldi-Carmona et al. Pharmacol. Exp. Ther. 1996, 278, 871-878 and M.M. Bouaboula et al., J. MoI. Biol. Chem. 1997, 272, 22330-22339, as demonstrated in vitro by results obtained in an adenylate cyclase inhibition model.

Weak penetration of the compound of formula (I) into the blood brain barrier (BBB) was evaluated in vivo by:
-Measurement (1): Quantification of compound of formula (I) (no change) in mouse brain samples after intravenous or oral administration by analytical technique (LC-MS / MS).

  A ratio of brain abundance / plasma abundance less than 0.2 indicates a weak penetration of the compound into the brain.

  -Measurement (2): M.M. Rinaldi-Carmona et al., FEBS Letters, 1994, 350, 240-244 and M.C. Rinaldi-Carmona et al., Life Sciences, 1995, 56, 1941-1947, M. et al. Rinaldi-Carmona et al. Pharmacol. Exp. Ther. , 2004, 310, 905-914 and ex vivo binding studies of [3H] -CP55940 (CB1 agonist) after intravenous administration (10 mg / kg) in the mouse brain Of interactions with CB1 receptors present in

  A [3H] -CP55940 binding inhibition rate in the brain of less than 50% at 10 mg / kg indicates weak penetration into the brain. This proportion is preferably less than 40%, more preferably less than 30%.

  -Measurement (3): M.M. As described in Rinaldi-Carmona et al., JPET 2004,310,905-914). Inhibition of blockade by a compound of formula (I) having a hypothermic effect induced by a CB1 receptor agonist (CP55940) after intravenous administration. measurement.

  If the recovery rate of the effect of CP55940 is less than 50% at 10 mg / kg, it indicates weak penetration into the brain. This proportion is preferably less than 40%, more preferably less than 30%.

  The interaction of the compound of formula (I) according to the invention with the CB1 receptor present in the periphery is Rinaldi-Carmona et al. Pharmacol. Exp. Ther. , 2004, 310, 905-914, as demonstrated in mice by measuring the blockade of the inhibitory effect induced by the CB1 receptor agonist (CP55940) on gastrointestinal transit after oral administration. If the recovery rate of the effect of CP55940 is greater than 50% at 10 mg / kg, it indicates that there is a significant antagonistic ability at the level of CB1 receptor present in the periphery. Preferably, the return rate is between 70% and 100%.

  The compounds of formula (I) are compatible with their use as pharmaceuticals.

  Thus, according to another aspect of the present invention, the subject of the present invention is a human pharmaceutical or veterinary medicine comprising a compound of formula (I) or an addition salt of a compound of formula (I) with a pharmaceutically acceptable acid. It is an academic drug.

Accordingly, the compounds of the present invention are useful for the treatment of diseases involving cannabinoid CB ₁ receptors in humans or animals (especially mammals, including but not limited to dogs, cats, horses, cows, sheep) or Can be used in prevention.

  For example, but not limited to, compounds of formula (I) are notably anxiety, depression, mood disorders, insomnia, delirium, obsessive compulsive disorder, general psychosis, schizophrenia, hyperactivity For the treatment of psychiatric disorders, including attention deficit hyperactivity disorder (ADHD) in children, and even for the use of psychotropic substances, especially substance abuse and / or substance dependence, including alcoholism and nicotine dependence Used as a psychotropic agent for the treatment of disorders related to the use of psychotropic substances.

  The compounds of formula (I) according to the invention can be used as medicaments for the treatment of migraine, stress, psychogenic illness, panic attacks, epilepsy, movement disorders, especially dyskinesia or Parkinson's disease, tremor and dystonia .

  The compounds of formula (I) according to the invention can also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular the treatment of senile dementia and Alzheimer's disease and also the treatment of attention disorders or consciousness disorders.

  Furthermore, the compounds of formula (I) can be used as neuroprotective agents in the treatment of ischemia and cranial trauma and in the treatment of acute or chronic neurodegenerative diseases including chorea, Huntington's chorea and Tourette syndrome.

  The compounds of formula (I) according to the invention can be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, inflammatory chronic pain, pain induced by anticancer therapy.

  The compounds of formula (I) according to the invention are particularly suitable for the prevention and treatment of appetite disorders, craving disorders (desire for sugars, carbohydrates, drugs, alcohol or any appetite-enhancing substance) and / or eating disorders, especially obesity or It can be used as a human or veterinary medicine for the treatment of bulimia and also for the treatment of type II diabetes or non-insulin dependent diabetes and the treatment of dyslipidemia and metabolic syndrome. The compounds of formula (I) according to the invention are therefore used in the treatment of obesity and the risks associated with obesity, in particular cardiovascular risks.

  Furthermore, the compounds of the formula (I) according to the invention can be used for gastrointestinal disorders, diarrheal disorders, ulcers, vomiting, bladder and urinary disorders, liver disorders which can be alcoholic or nonalcoholic, such as chronic cirrhosis, fibrosis, hepatic steatosis Or steatohepatitis; and even endocrine disorders, cardiovascular disorders, hypotension, atherosclerosis, hemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, Fertility disorder, premature birth, abortion, inflammatory phenomenon, immune system diseases, especially autoimmune diseases and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, demyelinating diseases, multiple sclerosis, infectious and viral As a pharmaceutical in the treatment and prevention of diseases such as encephalitis, stroke, and also anticancer chemotherapy, treatment of Guillain-Barre syndrome and bone disease and It can also be used as a medicament for the treatment of osteoporosis. Furthermore, the compounds of formula (I) according to the invention can be used for their protective effect against drug-induced cardiotoxicity.

  According to the invention, the compounds of formula (I) are most particularly in the prevention and treatment of mental disorders, in particular schizophrenia, attention disorders and consciousness disorders, attention deficit hyperactivity disorder (ADHD) in hyperactive children. In the prevention and treatment of memory impairment and cognitive impairment; in substance prophylaxis and withdrawal from substances, in particular alcohol dependence, nicotine dependence, alcohol withdrawal and tobacco withdrawal; in prevention and treatment of acute or chronic neurodegenerative diseases and Used in the preparation of pharmaceuticals used in therapy.

  More particularly, the compounds of formula (I) according to the present invention are suitable for the following: anorexia, craving disorders, metabolic disorders, obesity, type II diabetes, metabolic syndrome, dyslipidemia, gastrointestinal disorders, inflammatory phenomena, immune system diseases, mental disorders Used in the preparation of pharmaceuticals used in the treatment and prevention of alcoholism and nicotine addiction.

  According to one aspect of the invention, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of the disorders and diseases mentioned above.

  According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising a compound according to the invention as an active ingredient. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt of said compound and furthermore at least one pharmaceutically acceptable excipient. Related to things.

  Said excipients are selected from customary excipients known to the person skilled in the art according to the desired pharmaceutical form and administration method.

  In the pharmaceutical composition of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, topical, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) as defined above or Salts can be administered to animals and humans in unit dosage form as a mixture with conventional pharmaceutical excipients for the prevention or treatment of the disorders or diseases described above.

  Suitable unit dosage forms are oral dosage forms such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal dosage forms Dosage forms by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous dosage forms, rectal dosage forms and implants. For external application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unit dosage form of a compound according to the invention in tablet form may contain the following components:
Compound according to the invention: 50.0 mg
Mannitol: 223.75mg
Croscarmellose sodium: 6.0 mg
Corn starch: 15.0mg
Hydroxypropyl methylcellulose: 2.25mg
Magnesium stearate: 3.0mg
The dose of active ingredient administered per day via oral administration can be from 0.01 to 100 mg / kg, preferably from 0.02 to 50 mg / kg, including one or more intakes.

  There may also be particular cases where higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to customary practice, the appropriate dosage for each patient is determined by the physician according to the method of administration and the weight and response of the patient.

  According to another aspect of the present invention, the present invention also relates to a method of treating a pathological condition as described above, comprising administering to a patient an effective dose of a compound according to the present invention or a pharmaceutically acceptable salt thereof.

Claims (14)

Formula (I) in the form of a base or an addition salt with an acid:

(Where
-R ₁ is
· _-NR 5 _{R 6} groups;
Represents a phenyl which is unsubstituted or substituted one or more times by a substituent independently selected from a halogen atom, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy and trifluoromethyl. ;
-R ₂ is
· _(C 1 -C ₄₎ alkyl;
-Represents -X-R ₇ group;
-R ₃ and R ₄ are phenyl substituted one or more times by a substituent independently selected from a halogen atom, (C ₁ -C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxy and trifluoromethyl. Represents each independently;
- R ₅ represents a hydrogen atom or a _(C 1 -C ₄₎ alkyl;
-R ₆ represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted by one or more fluorine atoms or by phenyl which is unsubstituted or substituted by a halogen atom;
-Or else R ₅ and R ₆ together with the nitrogen atom to which they are attached constitute a heterocycle selected from azetidine, pyrrolidine and piperidine, said heterocycle being unsubstituted Or is substituted one or more times by a halogen atom;
- X _represents a _(C 1 -C ₅₎ alkylene;
- R ₇ is ₈ group _-OR, -NR _{9 R 10} group or _{-SO 2 - (C 1 -C 4} ) alkyl group;
- R ₈ represents a hydrogen atom or a _(C 1 -C ₄₎ alkyl;
- R ₉ represents a hydrogen atom or a _(C 1 -C ₄₎ alkyl;
- R ₁₀ represents a hydrogen atom, -COR _{11 group,} -SO _{2 R 11} group or -CO the _{(CH 2)} m OH groups;
-R ₁₁ represents (C ₁ -C ₄ ) alkyl which is unsubstituted or substituted by one or more fluorine atoms;
-M represents 1, 2 or 3. )
Compound. -R ₁ is
· _-NR 5 _{R 6} groups;
Represents phenyl;
R ₂ is
Methyl;
-Represents -X-R ₇ group;
-R ₃ and R ₄ each independently represent phenyl substituted once or twice by a halogen atom;
-R ₅ represents a hydrogen atom;
-R ₆ represents (C ₁ -C ₄ ) alkyl substituted by one or more fluorine atoms or by phenyl which is unsubstituted or substituted by a halogen atom;
-Or otherwise, R ₅ and R ₆ together with the nitrogen atom to which they are attached, an unsubstituted or substituted piperidin-1-yl group once or twice by a halogen atom Comprising:
- X is _represents a _(C 1 -C ₃₎ alkylene;
- R ₇ is, represents the ₈ group _-OR, -NR _{9 R 10} group or _-SO 2 -CH ₃ group;
-R ₈ represents a hydrogen atom;
-R ₉ represents a hydrogen atom;
- R ₁₀ is a hydrogen atom, -CO-CH ₃ group _represents -SO 2 -CH ₃ group or -COCH ₂ OH groups,
2. A compound of formula (I) according to claim 1 in the form of a base or in the form of an addition salt with an acid. -R ₁ is
_{· -NH (CH 2) 2 -CF} 3 group, 4-fluorobenzyl group, benzylamino group, piperidin-1-yl group, 4,4-difluoro-1-yl group;
Represents phenyl;
R ₂ is
Methyl;
-Represents -X-R ₇ group;
-R ₃ represents 4-chlorophenyl;
-R ₄ represents 2-chlorophenyl or 2,4-dichlorophenyl;
-X represents methylene, ethylene or trimethylene;
- R ₇ is, represents an -OH group, -NH ₂ group, -NHCOCH ₃ group, -NHSO ₂ CH ₃ group, -NHCOCH ₂ OH group or a _-SO 2 -CH ₃ group,
2. A compound of formula (I) according to claim 1 in the form of a base or in the form of an addition salt with an acid. 1 '-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3-methoxythien-2-yl] carbonyl} -1,4'-bipiperidine-4'-carboxamide;
-1 '-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {3-[(methylsulfonyl) amino] propoxy} thien-2-yl] carbonyl} -1,4 '-Bipiperidine-4'-carboxamide;
1 ′-({4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- [3- (methylsulfonyl) propoxy] thien-2-yl} carbonyl) -1,4′-bipiperidine -4′-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1-({4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- [3- (methylsulfonyl) propoxy] thien-2-yl} carbonyl) -4-phenylpiperidine-4- Carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1 ′-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4,4-difluoro-1,4 '-Bipiperidine-4'-carboxamide;
1 ′-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4,4-difluoro-1,4 '-Bipiperidine-4'-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-[(3,3,3- Trifluoropropyl) amino] piperidine-4-carboxamide;
1-({4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- [3- (methylsulfonyl) propoxy] thien-2-yl} carbonyl) -4-[(3,3 , 3-trifluoropropyl) amino] piperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {2- (hydroxyacetyl) amino] ethoxy} thien-2-yl] carbonyl} -4-[(3 , 3,3-trifluoropropyl) amino] piperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4-[(3,3,3- Trifluoropropyl) amino] piperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {2-[(hydroxyacetyl) amino] ethoxy} thien-2-yl] carbonyl} -3-phenylpiperidine -4-carboxamide;
1-{[3- (2-acetamidoethoxy) -4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino Piperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino Piperidine-4-carboxamide;
1-({4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- [3- (methylsulfonyl) propoxy] thien-2-yl} carbonyl) -4-[(4-fluoro Benzyl) amino] piperidine-4-carboxamide;
1-{[3- (2-acetamidoethoxy) -4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino Piperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {2-[(hydroxyacetyl) amino] ethoxy} thien-2-yl] carbonyl} -4-[( 4-fluorobenzyl) amino] piperidine-4-carboxamide;
1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {3-[(hydroxyacetyl) amino] propoxy} thien-2-yl] carbonyl} -4-[( 4-fluorobenzyl) amino] piperidine-4-carboxamide;
1-{[3- (3-acetamidopropoxy) -4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino Piperidine-4-carboxamide;
4- (benzylamino) -1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} piperidine-4- Carboxamide;
4- (benzylamino) -1-{[4- (4-chlorophenyl) -5- (2,4-dichlorophenyl) -3- {2-[(hydroxyacetyl) amino] ethoxy} thien-2-yl] Carbonyl} piperidine-4-carboxamide;
1-{[5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino] piperidine -4-carboxamide;
1-{[5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- (3-hydroxypropoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1-{[5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1-{[5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- (2-hydroxyethoxy) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino] piperidine -4-carboxamide;
1-{[3- (2-aminoethoxy) -5- (2-chlorophenyl) -4- (4-chlorophenyl) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino] piperidine -4-carboxamide;
1-{[3- (2-acetamidoethoxy) -5- (2-chlorophenyl) -4- (4-chlorophenyl) thien-2-yl] carbonyl} -4-[(4-fluorobenzyl) amino] piperidine -4-carboxamide;
1-{[3- (2-aminoethoxy) -5- (2-chlorophenyl) -4- (4-chlorophenyl) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1-{[5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- {2-[(hydroxyacetyl) amino] ethoxy} thien-2-yl] carbonyl} -4-phenylpiperidine-4 A carboxamide;
1-{[3- (2-acetamidoethoxy) -5- (2-chlorophenyl) -4- (4-chlorophenyl) thien-2-yl] carbonyl} -4-phenylpiperidine-4-carboxamide;
1-{[5- (2-chlorophenyl) -4- (4-chlorophenyl) -3- {2- (hydroxyacetyl) amino] ethoxy} thien-2-yl] carbonyl} -4-[(4-fluoro A compound according to claim 1, in the form of a base or in the form of an addition salt with an acid, selected from benzyl) amino] piperidine-4-carboxamide. A process for preparing a compound of formula (I) according to claim 1 comprising
formula:

Wherein R ₁ , R ₃ and R ₄ are as defined for the compound of formula (I) according to claim 1 in the presence of a base:
Z-R ₂ (III)
A process comprising reacting with a compound of the formula wherein R ₂ is as defined for the compound of formula (I) according to claim 1 and Z represents a leaving group. A process for preparing a compound of formula (I) according to claim 1 comprising
formula:

Wherein R ₂ , R ₃ and R ₄ are as defined for the compound of formula (I) according to claim 1, or a functional derivative of this acid of the formula:

A process characterized in that it is reacted with a compound of the formula (wherein R ₁ is as defined for the compound of formula (I) according to claim 1).   A pharmaceutical product comprising a compound of formula (I) according to any one of claims 1 to 4 or an addition salt of this compound of formula (I) with a pharmaceutically acceptable acid.   Addition salt of a compound of formula (I) according to any one of claims 1 to 4 or a compound of formula (I) with a pharmaceutically acceptable acid and also at least one pharmaceutically acceptable salt. A pharmaceutical composition comprising an excipient.   5. The preparation of a medicament for use in the treatment and / or prevention of psychiatric disorders, substance dependence and withdrawal from substances, cognitive disorders, attention disorders and consciousness disorders and acute and chronic neurodegenerative diseases. Use of a compound according to any one of the above.   5. Any one of claims 1 to 4 for the preparation of a medicament for use in the treatment and / or prevention of metabolic disorders, appetite disorders, desire disorders, obesity, bulimia, diabetes, metabolic syndrome and dyslipidemia. Use of the compounds described in 1.   Any one of claims 1 to 4 for the preparation of a medicament for use in the treatment and / or prevention of pain, neuropathic pain, acute peripheral pain, inflammatory chronic pain and pain induced by anticancer therapy. Use of the compound according to item.   Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for use in the treatment and / or prevention of gastrointestinal disorders, vomiting, diarrheal disorders, ulcers and liver disorders.   Any of claims 1 to 4 for the preparation of a medicament for use in the treatment and / or prevention of inflammatory phenomena, immune system diseases, rheumatoid arthritis, demyelinating diseases, multiple sclerosis, bone diseases and osteoporosis Use of a compound according to one paragraph.   5. A compound according to any one of claims 1 to 4 for the preparation of a medicament for use in the treatment and / or prevention of movement disorders and movement disorders, in particular dyskinesia or Parkinson's disease, senile dementia and Alzheimer's disease. Use of.